PROJECT SUMMARY/ABSTRACT The overall goal of this proposal is to determine the predominant anatomic site (liver or skeletal muscle) of insulin resistance and the mechanisms that lead to its development in men with prostate cancer (PCa) undergoing androgen deprivation therapy (ADT). As testosterone has a central role in the stimulation of prostate tissue, ADT is the cornerstone of treatment in men with high grade and metastatic PCa. ADT results in castrate levels of serum testosterone and this profound androgen deficiency leads to an increase in both visceral and subcutaneous fat mass, and a reduction in skeletal muscle mass. These unfavorable changes in body composition result in the development of insulin resistance and cardiovascular disease. These metabolic perturbations follow an aggressive course in these men as insulin resistance develops within 8 weeks of starting ADT. These adverse metabolic changes have significant consequences as men on ADT have a higher risk of cardiovascular disease including coronary artery disease, myocardial infarction, peripheral vascular disease and sudden cardiac death compared with those men with PCa who do not undergo ADT and are only treated with prostatectomy (non-ADT group). Indeed, cardiovascular disease has become the leading cause of mortality in these men. Although insulin resistance is the seminal event in this metabolic cascade, the predominant site and the mechanisms behind its development (such as the role of parenchymal fat infiltration and inflammatory cytokines) remain unknown in this patient population. As men undergoing ADT are old, frail and have multiple co-morbidities, the option of physical exercise is limited in these men. Hence, unveiling the site and the mechanisms of this resistance will guide physicians to prevent insulin resistance by initiating tissue-specific insulin sensitizing drugs in the future. We propose a prospective, 6-month, observational cohort study in which we will: 1) determine the predominant site of insulin resistance by using a validated, state-of-the-art, oral glucose tolerance test, and 2) determine the mechanism of insulin resistance by measuring hepatic and intramyocellular fat (using magnetic resonance spectroscopy) and measuring circulating inflammatory cytokines (known to induce insulin resistance in other populations) by using validated assays. The information obtained from this study will not only lead to future mechanistic studies at the cellular level of the implicated organ, but also lay the framework for clinical trials evaluating the role of evolving tissue- specific insulin-sensitizers and novel anti-inflammatory drugs in the prevention and treatment of insulin resistance, which in turn, will prevent cardiovascular disease in these men.